Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model

1 Division of Bioengineering and Physical Science, Office of Research Services, 2 Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, and 3 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 Submitted 7 August 2002 ; accepted in final form 4 March 2003 Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 µl/min), the distribution of cytotoxicity in NK 1 receptor-expressing neurons was predicted to reach an asymptotic limit at 6–8 h in the transverse direction at the level of the infusion cannula tip ( 60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life 60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK 1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain. convection-enhanced delivery; intraparenchymal infusions; pain therapy; pharmacodynamic model; convection; finite-element method Address for reprint requests and other correspondence: M. Sarntinoranont, Drug Delivery and Kinetics Resource, Div. of Bioengineering and Physical Science, ORS, NIH, Bldg. 13, Rm. 3N17, 13 South Dr., Bethesda, MD 20892-5766 (E-mail: sarntinm{at}mail.nih.gov ).